Simultaneous treatment with eculizumab and cemdisiran may benefit patients with paroxysmal nocturnal hemoglobinuria (PNH) who do not respond well to eculizumab alone, according to an article published in eJHaem.

This phase 1/2 study assessed the safety and tolerability of cemdisiran, as well as the change in complement activity, lactate dehydrogenase levels, and inhibition of hemolysis following cemdisiran treatment.

The study design comprised 3 parts. In part A, the researchers evaluated a single ascending dose (50-900 mg) of cemdisiran or placebo in 32 healthy adults. Part B evaluated multiple ascending doses (100–600 mg) of cemdisiran or placebo in 24 healthy adults, while part C evaluated cemdisiran in 6 patients with PNH who were naive to, or receiving, eculizumab (200 or 400 mg weekly).

According to the results, the medication yielded sustained reductions in the complement activity of healthy adults and patients with PNH. As evidenced by lactate dehydrogenase levels in part C, cemdisiran monotherapy could not prevent hemolysis in patients with PNH but the combination of cemdisiran and eculizumab reduced the dose of eculizumab required to provide adequate control of intravascular hemolysis.

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Cemdisiran was safe and well-tolerated with 75%, 89%, and 100% of subjects in parts A, B, and C, respectively, experiencing at least 1 nonserious adverse event. The most common adverse events included grade 1 or 2 nasopharyngitis and headache.

“This study highlighted the importance of blocking complement activity in PNH, as near complete C5 inhibition was required to reduce lactate dehydrogenase below the upper limit of normal. Other complement-mediated diseases (e.g., myasthenia gravis, IgA nephropathy) may require a lower degree of C5 suppression compared with PNH because of differences in target cell types, as nucleated cells are more resistant to the membrane attack complex attack than anucleated red blood cells,” Gaya and colleagues noted.

PNH, caused by complement dysregulation, is treated by inhibitors targeting C5 and C3 such as eculizumab, ravulizumab, and pegcetacoplan. However, these therapies come with a burden of intravenous administration and some patients still experience intravascular hemolysis at the end of a treatment cycle.


Gaya A, Munir T, Urbano-Ispizua A, et al. Results of a phase 1/2 study of cemdisiran in healthy subjects and patients with paroxysmal nocturnal hemoglobinuria. EJHaem. Published online June 26, 2023. doi:10.1002/jha2.748